Clinical Outcomes and Genetic Contribution in Mood Disorders: The Role of Sleep Features
Date Issued
2015
Date
2015
Author(s)
Lai, Yin-Chieh
Abstract
Sleep problems are commonly observed in mood disorder patients, the sleep profiles among subgroups (major depressive (MDD), bipolar disorder (BD) patients, their relatives, and controls) and the familiality of sleep problems in MDD and BD families have not been well known. Sleep disturbance is important because it impairs quality of life (QOL), contributes to relapse, and has adverse consequences. Moreover, less is known about the longitudinal time effect between sleep and mood change. Sleep disturbance has caused by abnormal circadian function in mood disorders. Several genes that are involved in the regulation of circadian rhythms implicated in the susceptibility to mood disorders and sleep related problems. This suggests a connection between proper mood regulation and a normal functioning circadian clock. While sleep disturbance and circadian dysregulation are critical pathophysiological elements in mood disorders, many questions about the sleep profiles and the mechanisms remain. The current study aimed to explore the role of sleep in clinical outcomes and genetic contribution in mood disorders. First, we compare the sleep disturbances among subgroups and evaluated familiality in MDD and BD families. We examined the associations of sleep quality and patients’ QOL and functional impairment. Second, we evaluated the time effects of sleep and mood, and whether poor sleepers predict poorer clinical outcomes at follow up period. Third, we investigated the relationships between genetic variants in circadian genes with BD and with sleep phenotypes in the Han Chinese population. We recruited around ~1300 participants, including around ~700 probands ( ~350 DSM-IV diagnosed BD-I, 150 BD-II, and 200 MDD), 618 relatives and 235 healthy controls were completed structural diagnostic interview, sleep measurements including Pittsburgh Sleep Quality Index (PSQI), and Mornigness－Eveningness scale (M/E scale); the severity of symptoms measurements including Beck Depression Inventory (BDI-II), and Young Mania Rating Scale (YMRS); and World Health Organization Quality of Life brief version (WHOQOL) questionnaires. Single nucleotide polymorphisms in the circadian genes were genotyped using Affymetrix Genome-Wide CHB Array. Familiality of components of sleep was evaluated using mixed regression models and intraclass correlation coefficients (ICC). The relation of sleep on symptom severity and impairments during the same interval longitudinally across the 6-month period was also examining by mixed regression models. Genetic association analyses were performed using PLINK software. Three-quarter of mood disorder patients divided to “poor sleepers”, and with worse QOL and more functional impairment (p<0.01) than good sleepers. MDD patients had significantly worse sleep quality than BD patients, whereas there was no difference between unaffected relatives and controls. Moderate familial aggregation observed in subjective sleep quality, sleep latency and disturbance. Sleep disturbances such as poor sleep quality and nightmares increased the risk for suicidal ideation and suicide attempts. After a six month follow up, the persistence rates of sleep disturbance were 77.8% and 82.60% in BD and MDD, respectively. Multivariate analyses in linear/logistic regression models revealed that sleep disturbances at baseline including global score and frequent nightmares were significantly increased the consequence of depression (OR=1.07-4.56), suicide ideation (OR= 1.25-3.35) and suicide plan (OR= 1.20-6.21). A longitudinal relationship was showed of global score with poor clinical outcomes expect mania during the follow up. Our data suggested the idea that chronotypes have an impact on depressive features, with higher severity of depressive and suicide ideation for the eveningness type. For genetic association analysis, there were five genes (ARNTL2, BHLHE41, CNR1, RORA, RORB) showed significant with BD. Our results support for the involvement of RORs family in the risk of developing BD. For sleep phenotypes, we found ARNTL, ARNTL2, CNR1, CRY1, CSNK1E, CSNK2A1, GSK3b, NPAS2, PER3, RORA, RORB, TIMELESS, TIPIN genes with positive associations. Due to the notable sleep problems in mood disorders and the patients with sleep disturbances heightened the risk of recurrence and suicidality was demonstrated in the study. The special sleep intervention in mood disorders is required in clinical settings. The genes in circadian pathway may be an important candidate. Further replication studies are needed to investigate the functional properties of the genes in studying the pathogenesis of mood disorders and sleep problems.
Subjects
Major depressive disorder
Bipolar disorder
Circadian
Sleep disturbance
Familial aggregation
Longitudinal study
Genetic association
SDGs
Type
thesis